Early Breast Cancer Detection Using Untargeted and Targeted Metabolomics.

Breast cancer (BC) is a common cause of morbidity and mortality, particularly in women. Moreover, the discovery of diagnostic biomarkers for early BC remains a challenging task. Previously, we [Jasbi et al. J. Chromatogr. B. 2019, 1105, 26-37] demonstrated a targeted metabolic profiling approach capable of identifying metabolite marker candidates that could enable highly sensitive and specific detection of BC. However, the coverage of this targeted method was limited and exhibited suboptimal classification of early BC (EBC). To expand the metabolome coverage and articulate a better panel of metabolites or mass spectral features for classification of EBC, we evaluated untargeted liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) data, both individually as well as in conjunction with previously published targeted LC-triple quadruple (QQQ)-MS data. Variable importance in projection scores were used to refine the biomarker panel, whereas orthogonal partial least squares-discriminant analysis was used to operationalize the enhanced biomarker panel for early diagnosis. In this approach, 33 altered metabolites/features were detected by LC-QTOF-MS from 124 BC patients and 86 healthy controls. For EBC diagnosis, significance testing and analysis of the area under receiver operating characteristic (AUROC) curve identified six metabolites/features [ethyl (R)-3-hydroxyhexanoate; caprylic acid; hypoxanthine; and m/z 358.0018, 354.0053, and 356.0037] with p < 0.05 and AUROC > 0.7. These metabolites informed the construction of EBC diagnostic models; evaluation of model performance for the prediction of EBC showed an AUROC = 0.938 (95% CI: 0.895-0.975), with sensitivity = 0.90 when specificity = 0.90. Using the combined untargeted and targeted data set, eight metabolic pathways of potential biological relevance were indicated to be significantly altered as a result of EBC. Metabolic pathway analysis showed fatty acid and aminoacyl-tRNA biosynthesis as well as inositol phosphate metabolism to be most impacted in response to the disease. The combination of untargeted and targeted metabolomics platforms has provided a highly predictive and accurate method for BC and EBC diagnosis from plasma samples. Furthermore, such a complementary approach yielded critical information regarding potential pathogenic mechanisms underlying EBC that, although critical to improved prognosis and enhanced survival, are understudied in the current literature. All mass spectrometry data and deidentified subject metadata analyzed in this study have been deposited to Mendeley Data and are publicly available (DOI: 10.17632/kcjg8ybk45.1).

Association of magnesium consumption with type 2 diabetes and glucose metabolism: A systematic review and pooled study with trial sequential analysis.

Prevention of type 2 diabetes (T2D) with diet or diet supplementation is challenging. This article aims to draw conclusive associations between magnesium intake and T2D incidence and evaluate the effect of magnesium supplementation on glucose metabolism. Databases were searched for related articles from inception to May 15, 2019. Prospective cohort studies investigating the relevant relationship as well as randomized controlled trials (RCTs) assessing the effect of magnesium supplementation were eligible. We conducted trial sequential analysis (TSA) to prove the sufficiency of the current evidence. Twenty-six publications involving 35 cohorts were included in the analysis. Compared to the lowest magnesium intake, the highest level was associated with a 22% lower risk for T2D; the risk was reduced by 6% for each 100 mg increment in daily magnesium intake. Additional analysis of 26 RCTs (1168 participants) was performed, revealing that magnesium supplementation significantly reduced the fasting plasma glucose (FPG) level (SMD, -0.32 [95% CI, -0.59 to -0.05], 2-hour oral glucose tolerance test (2-h OGTT) result (SMD, -0.30 [-0.58 to -0.02]), fasting insulin level (SMD, -0.17 [-0.30 to -0.04]), homeostatic model assessment-insulin resistance (HOMA-IR) score (SMD, -0.41 [-0.71 to -0.11]), triglyceride (TG) level, systolic blood pressure (SBP) and diastolic blood pressure (DBP). TSA showed an inverse association, with most benefits of magnesium supplementation on glucose metabolism being stable. In conclusion, magnesium intake has an inverse dose-response association with T2D incidence, and supplementation appears to be advisable in terms of glucose parameters in T2D/high-risk individuals.